The present invention relates to novel fatty acid analogues which can be used for the treatment and/or prevention of primary and secondary stenosis. Further, the present invention relates to the use of said analogues for the treatment of diseases caused by procedural vascular trauma, and more specifically the invention relates to conditions associated with smooth muscle cell proliferation.
Many pathological conditions have been found to be associated with smooth muscle cell proliferation. Such conditions include restenosis, atherosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke, smooth muscle neoplasms such as leiomyoma and leiomyosarcoma of the bowel and uterus and uterine fibroid or fibroma.
Over half a million interventional intravascular procedures are performed each year. While such invasive procedures continue to improve over time, as many as 30-50% of the procedures performed each year fail as a result of restenosis, i.e. the formation of secondary stenosis. The reduction of restenosis is, therefore, often cited as the most critical factor in increasing the success realised in the treatment of cardiovascular disease through the use of interventional intravascular procedures, such as angioplasty, atherectomy, and procedures utilising stents and laser technology.
In balloon angioplasty, e.g. Percutaneous Transluminal Coronary Angioplasty (PTCA), a small incision is made to an artery in the patient""s leg or arm and a long hollow tube, called a guide catheter, is inserted into the artery. A thick guide wire and deflated balloon catheter are then inserted into the guide catheter and are carefully advanced through the patient""s blood vessels using x-ray visualisation. The deflated balloon is advanced until it reaches the site of the luminal narrowing, at which point the physician inflates the balloon one or more times to a pressure of about 4-6 atm for about 60 sec. When inflated, the balloon cracks and fractures the plaque and stretches the muscle fibre in the artery wall beyond its ability to recoil completely. Although no plaque is removed in this procedure, the fracturing of the plaque and the stretching of the arterial wall increase the vessel lumen, thereby allowing for increased blood flow.
The restenosis that accompanies such procedures is characterised by platelet aggregation and adhesion, smooth muscle cell proliferation, narrowing of the vessel lumen, restricted vasodilatation, and an increase in blood pressure. Smooth muscle cells in the intimal layer of the artery have been reported to enter the growth cycle within about 2-3 days of these procedures and to proliferate for several days thereafter (intimal hyperplasia).
Compounds that reportedly suppress smooth muscle proliferation in vitro may have undesirable pharmacological side effects when used in vivo. Heparin is an example of one such compound, which reportedly inhibits smooth muscle cell proliferation in vitro but when used in vivo has the potential adverse side effect of inhibiting coagulation.
As is apparent from the foregoing, many problems remain to be solved in the use of inhibitory drugs to effectively treat smooth muscle cell mobilisation and proliferation. It would be highly advantageous to develop new compositions or methods for inhibiting stenosis, restenosis or related disorders due to proliferation and mobilisation of vascular smooth muscle cells following, for example, traumatic injury to vessels rendered during vascular surgery.
Treatment with modified fatty acids represent a new way to treat these diseases.
EP 345.038 and PCT/NO95/00195 describes the use of non-xcex2-oxidizable fatty acid analogues for the treatment of hyperlipidemic conditions.
It has now been found that these fatty acid analogues have broader area of applications.
Further, we have now synthesised and characterised novel fatty acid analogues.
In feeding experiments with the fatty acid analogues of the present invention, the results show that these compounds lower the adipose tissue mass and body weight, and are thus potent drugs for the treatment of obesity and overweight. These results are described and claimed in the Applicants co-pending application PCT/NO99/00135.
We have also shown that the fatty acid analogues are potent antidiabetic compounds, with a profound effect on the levels of glucose and insulin. These results are described and claimed in the Applicants co-pending application PCT/NO99/0136.
We have shown that the compounds of the present invention inhibit the formation of secondary stenosis, and the present application thus relates to the use of these compounds for the prevention and/or treatment of restenosis. Further, we have shown that the compounds inhibit the proliferation and mobilisation of smooth muscle cells, and lower the concentration of plasma homocysteine. It is thus anticipated that the compounds also will have a preventive and/or therapeutic effect on primary stenosis. Further, it is anticipated that the present compounds will be useful for the treatment and/or prevention of atherosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke and smooth muscle cell neoplasms, and also diseases caused by procedural vascular trauma.
The novel compounds of the present invention are characterised by minor modifications of the natural fatty acids. Sulphur, selenium or oxygen are preferably substituted for one or more of the carbons in the fatty acid backbone. The compounds defined by the formula I have properties which give them a unique combination of biological effects.
Tetradecylthioacetic acid (TTA) and tetradecylselenioacetic acid (TSA) are most thoroughly studied, and we have shown several beneficial effects in various model animal systems.
The studies have shown that TTA has properties very similar to natural fatty acids, the main difference being that TTA is not oxidised by the mitochondrial xcex2-oxidation system. However, the presence of compounds of the present invention have been shown to increase the xcex2-oxidation of other (non-substituted) fatty acids.
Administration of TTA to rats for 12 weeks nearly doubled the hepatic and plasma content of monounsaturated fatty acids (mainly oleic acid), while polyunsaturated fatty acids (mainly linoleic acid and DHA) decreased. Thus the compound of the present invention modifies the composition of the lipids in various tissues.
Feeding moderate doses of TTA to animals like rats, mice, rabbits and dogs decreased both plasma cholesterol and triacylglycerol levels within days of treatment. We have also shown the same effect for TSA, and compounds of the present invention with Sulphur substituted in positions 5 or 7 have been shown to increase the xcex2-oxidation, and it is thus anticipated that also these fatty acid analogues will lower the plasma levels of triacylglycerols and cholesterol. TTA and TSA are far more potent in this respect than polyunsaturated fatty acids like EPA.
The experimental data of the present invention have unexpectedly revealed that the formation of secondary stenosis (restenosis) after angioplasty is markedly reduced or inhibited in various model animals given the compounds of formula I either orally or locally. This is clearly demonstrated in the experimental section, examples 3 and 4, which demonstrates that the artery diameter, several weeks after the angioplasty procedure, is maintained for animals given TTA, while the diameter is markedly reduced for control animals. These in vivo results clearly demonstrate the potential of these compounds for the prevention of the formation of secondary stenosis.
The action mechanisms for the formation of restenosis after PTCA are not completely understood, but it have been shown that restenotic lesions has an overgrowth of smooth muscle cells in the intimal layers of the vessel.
We have shown that the compounds of the present invention reduce the growth and mobilisation of smooth muscle cells. Increased smooth muscle cell proliferation has also been associated with atherosclerosis, coronary heart disease, thrombosis, myocardial infarction and stroke.
Normal blood vessels are lined with a layer of endothelial cells. The endothelium releases local factors such as nitric oxide, prostaglandin I2 and prostacyclin into the vessel wall (intramural release) and into the blood stream (intraluminal release). These factors maintain vascular tone (vessel relaxation), inhibit clot formation on the vessel inner surface (platelet adhesion and aggregation), inhibit monocyte adherence and chemotaxis, and inhibit smooth muscle cell migration and proliferation. As a result of this process, vasodilation and thrombolysis occurs, and blood flow is maintained. If the endothelium is dysfunctional or damaged, however, nitric oxide and prostacyclin release is impaired. Platelet aggregation and adhesion can occur unopposed, with platelet-derived products acting directly on the smooth muscle cells to cause vasoconstriction. The net result is a blood vessel which is highly susceptible to thrombosis and vasospasm.
Atherosclerosis can form within a blood vessel over a period of years from a variety of causes. The resulting lesion, or plaque, may progressively occlude the vessel and impede blood flow to vital organs.
The described vasoconstrictive physiologic mechanisms occur both in peripheral and in coronary arteries, but the consequences of the processes are more life threatening in the coronary arteries. Coronary arteries, the arteries of the heart, perfuse the cardiac muscle with oxygenated arterial blood. They provide essential nutrients and allow for metabolic waste and gas exchange. These arteries are subject to unremitting service demands for continuous blood flow throughout the life of the patient. A severe proximal coronary stenosis with endothelial injury induces cyclic coronary flow reductions (xe2x80x9cCFR""sxe2x80x9d). These are periodic or spasmodic progressive reductions in blood flow in the injured artery. Episodes of CFR""s are correlated to clinical acute ischemic heart disease syndromes, which comprise unstable angina, acute myocardial infarction and sudden death. The common pathophysiologic link is endothelial injury with vasospasm and/or thrombus formation.
It is thus anticipated and claimed that the compounds of the present invention by its action on the smooth muscle cells will have a favourable effect on the group of diseases mentioned above.
As indicated, the present compounds also exhibit a lipid lowering effect, and the administration of a compound of the present invention is thus the compound of choice for the treatment or prevention of artery related diseases. The low toxicity of these compounds makes them very suitable as prophylactically agents given to mammals in need thereof, e.g. to prevent the formation of primary stenosis.
We have also demonstrated that the compounds of the present invention decrease the plasma concentration of homocysteine. Elevated levels of homocysteine are considered as a risk factor for, and are correlated with the development of atherosclerosis. Thus, based on this homocysteine lowering effect of TTA it is anticipated that the present compounds will have a inhibiting effect on the formation of primary stenosis.
The present invention discloses that modified fatty acid analogues at non-cytotoxic concentrations can be used for the treatment and/or prevention of stenosis and restenosis.
We have also shown that the compounds of the present invention reduces the proliferation and mobilisation of smooth muscle cells, and it is known that proliferation of smooth muscle cells is a pathological factor in diseases such as atherosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke and smooth muscle cell neoplasms, and the treatment and/or prevention of such diseases by the use of the compounds of formula (I) are also part of the present invention.
The present invention relates to the use of fatty acid analogues of the general formula (I):
CH3xe2x80x94[CH2]mxe2x80x94[Xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number which indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug and complex thereof, for the preparation of a pharmaceutical composition for the treatment and/or prevention of primary and/or secondary stenosis.
In particular, the invention relates to the use of a compound of the general formula I, for the treatment and/or prevention of a disease caused by procedural vascular trauma and/or pathological proliferation of smooth muscle cells and/or an increased level of plasma homocysteine.
Preferred embodiments of the invention relate to the use of a compound of the general formula I, wherein the diseases are selected from the group comprising atherosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke, vascular dementia and smooth muscle cell neoplasms.
One embodiment of the invention is the use of a compound of formula I wherein mxe2x89xa713.
A presently preferred embodiment of the invention comprises the formula I, wherein Xi=3 is selected from the group consisting of O, S, SO, SO2 and Se, and wherein Xi=5-25 is CH2.
Tetradecylthioacetic acid (TTA) and Tetradecylselenoacetic acid (TSA), i. e. Xi=3 is Sulphur and Selenium, respectively are presently preferred compounds.
A further aspect of the invention relates to a method for the prophylactic or therapeutic treatment of primary or secondary stenosis in a mammal, said method comprising the step of administering to a mammal in need thereof an effective amount of fatty acid analogues of the general formula (I):
CH3xe2x80x94[CH2]mxe2x80x94[Xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number which indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug or complex thereof.
The treatment involves administering to a patient in need of such treatment an effective concentration which is maintained substantially continuously in the blood for the duration of the period of its administration.
Further, the invention relates to a pharmaceutical composition for the prevention and/or treatment of a primary and/or secondary stenosis. Preferably, the pharmaceutical composition comprises in admixture with the fatty acid analogues a pharmaceutically acceptable carrier or excipient.
The invention also relates to novel fatty acid analogues of the formula I
CH3xe2x80x94[CH2]mxe2x80x94[XiCH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number which indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug or complex thereof.